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Principles and Application of Radiation Therapy
Symposium on Clinical Veterinary Oncology
Principles and Application of Radiation Therapy
Donald E. Thrall, D.V.M., Ph.D.,* and Darryl N. Biery, D.V.M.t
Radiotherapy in veterinary medicine is not enjoying the same degree of popularity that it is in human medicine. This is due to three factors: economics, lack of a unified organized approach to the problem of cancer in animals, and a general lack of knowledge regarding the usefulness of radiotherapy in veterinary medicine.
Economics No one can argue the importance of economics relative to the practice of certain aspects of veterinary medicine. This is particularly true regarding radiotherapy which necessitates costly equipment and the charge to the client routinely involves many hundreds of dollars. ~evertheless, many clients are willing to tolerate the expense and opt for radiotherapy. Therefore, the teaching centers of veterinary medicine have some obligation to the public to provide a competent radiotherapy service and practitioners of veterinary medicine have an obligation to make the owner of an animal with cancer aware of radiotherapy.
Lack of an Organized Approach Ten years ago there was no question that an organized approach to the management of animal cancer did not exist. This is not true today as evidenced by the recent formation of the Veterinary Cancer Society and this symposium on veterinary clinical oncology. The structure of an organized approach to the problem of animal cancer is covered elsewhere in this symposium; however, it is important here to *.\ssistant Professor of Radiology, School of Veterinary Medicine and School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania "'.\ssociate Professor and Chief, Section of Radiology, School of Veterinary Medicine, and Associate Professor of Radiological Science, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania l"eterinary Clinics of North America- Vol. 7, No. 1, February 1977
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stress the value of the cooperation of the private practitioner regarding the success of such a program.
Lack of Knowledge Regarding Usefulness of Radiotherapy It is little surprise that many practicing veterinarians have minimal appreciation for the usefulness of radiotherapy in the management of the cancer patient. This stems from the fact that for many years radiotherapy was not stressed by the veterinary schools themselves. Hopefully this paper will enhance the general appreciation of the usefulness of radiotherapy in the management of the cancer patient.
PRINCIPLES There is nothing mystical about the ability of or method by which radiation kills cells. All radiations used to treat cancer produce ions in the tissue in which they interact and thus are termed ionizing radiation. An ion is simply an atom with an excess of deficiency of electrons. Ionizing radiation produces ions by removing electrons from atoms, and is either directly or indirectly ionizing. Directly ionizing radiation is particulate and charged (e.g., electrons, alpha particles, and ?T-mesons) and produces direct atomic disruption in the tissue through which it passes. Indirectly ionizing radiation (e.g., x-rays, gamma rays, and neutrons) does not produce the majority of atomic disruption itself but does so via high speed charged particles to which it transfers energy in the body. In veterinary medicine most radiotherapy utilizes x-rays and gamma rays. Both x-rays and gamma rays are electromagnetic radiation with wave lengths less than 1o-s em. Radio waves, radar waves, and visible light waves are also electromagnetic radiation but are not capable of producing ions due to their longer wave length and lower energy. The physical and biologic properties of x-rays and gamma rays are essentially identical. The x and gamma simply refer to the site of production of the radiation. X-rays are produced outside the nucleus of an atom by an interaction involving a high speed electron and gamma rays are produced in the nucleus of an atom and represent a method by which an unstable nucleus may rid itself of excess energy. The actual amount of physical damage introduced into tissue by therapeutic doses of ionizing radiation is negligible. For example, the energy deposited in tissue by 1000 rads ( 1 rad equals the absorption of 1000 ergs of energy per gm of tissue) raises the temperature of the tissue only about 0.001° C. This dose of radiation, however, will easily kill the largest man if administered to his entire body. Therefore, there must be some biologic amplification which enhances the initial damage produced. At this time most radiobiologists favor the theory that the lethal lesion in the cell is disruption of nuclear DNA. This can occur
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when relatively little energy is deposited in the DNA and has the potential for becoming lethal to the cell when the cell tries to divide. Thus the biologic amplification of the initial energy deposition is mediated through damage to DNA and culminates in cell death when the cell attempts to divide. Radiation kills both normal and neoplastic cells to about the same extent. In most cases tumor cells are not more sensitive than normal cells to the killing effects of radiation. This poses no problem in terms of killing a tumor with radiation. Any tumor can be killed with radiation provided the dose is high enough. The problem this lack of differential sensitivity does impose is how to selectively kill a tumor with radiation while sparing sufficient normal tissue to repair the defect produced by killing the tumor. Two approaches to solving this problem are dividing the total dose into smaller fractions separated by a certain period of time (i.e., fractionation) and implanting radioactive material directly into the tumor. Two factors which have some influence on the inherent radiosensitivity of cells are the position of the cell in the cell division cycle and the oxygenation level of the cell. In terms of the cell division cycle, the most radiosensitive phase is during mitosis and the most radioresistant phase is late during the period of DNA synthesis. As of this date, no one has been able to put this cell-cycle related fluctuation of radiosensitivity to therapeutic use. On the other hand, differences in oxygen tension may be very important in determining whether a tumor can be cured with radiation. Viable hypoxic cells require two to three times more radiation to be killed than do aerobic cells. Hypoxic viable cells do exist in spontaneous tumors of animals. It is these cells that may survive a course of radiation and lead to recurrence of the tumor. Fractionation may lead to destruction of the hypoxic cell compartment by allowing the hypoxic cells to become reoxygenated in the intertreatment interval and therefore more sensitive to the killing effects of the radiation given during the next fraction. Contrary to popular belief, many types of tumor cells are actually dividing more slowly than are the surrounding normal tissues. Or, on the other hand, if the tumor cell population is dividing more rapidly than the normal cell population before irradiation, the situation may reverse itself after irradiation due to homeostatic shortening of the division rate of the normal cell production. Both situations are conducive to the success of fractionating the x-ray dose because in the intertreatment interval the more rapidly dividing normal tissue cells are capable of increasing their total cell number relative to the neoplastic cell number. The alternative solution to the problem of similar radiosensitivity of normal and tumor cells is the implantation of radioactive substances into the tumor. This technique, of course, would deposit a larger radiation dose into the tumor relative to the normal tissue and would favor sterilization of the tumor.
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As implied in the above discussion, the single limiting factor regarding the probability of satisfactory tumor cure by radiotherapy is the amount of radiation that can be tolerated by the surrounding normal tissue.
INDICATIONS AND SELECTION OF PATIENTS Radiotherapy is looked upon by some as a "last ditch" effort to be reserved for use in cases in which all else has failed. Previous reports of cure rates of animal tumors treated with radiation indicate that this should not be the case. L 3-5 • 8 On the other hand, radiotherapy is not a panacea for cancer. Radiotherapy occupies a distinct and well defined niche in the armamentarium of the oncologist. The first step in determining the applicability of radiotherapy in an animal with cancer is the performance of a thorough physical examination. Particular attention must be paid to the presence or absence of metastatic disease. To do this accurately one must possess an explicit knowledge of the mechanisms of the spread of disease. All too often regional nodes are overlooked. Generally speaking, the animal should be in relatively good health before any treatment is initiated. After the general evaluation is complete, the tumor should be evaluated primarily for its size, location, and invasiveness. A biopsy must be obtained to document that one is in fact dealing with a malignancy, to gain insight as to how the tumor is likely to metastasize, and for prognosis. Usually the tumor cell type in itself has little to do with the modality chosen to treat the tumor. After a definitive diagnosis of malignancy is made the next decision is to choose between aggressive therapy and euthanasia. These are the only two choices that warrant consideration since any therapy that is instituted should be aggressive. This decision should be made by the client after all options and pertinent information have been made known by the veterinarian. Not every tumor is amenable to radiotherapy. In general, widely disseminated neoplasia, such as lymphosarcoma, granulocytic leukemia, and metastatic disease, can only be treated chemotherapeutically. Tumors that are well localized and have not extensively invaded adjacent structures are best treated surgically. Tumors that are well localized and relatively superficially located but are locally invasive are best treated by radiotherapy. Obviously all tumors do not fall into one of the above three categories. In these cases two, or even three, of the above modalities can be combined for optimal management of the tumor. In general, radiotherapy is reserved as the primary modality for tumors not so large than an excess amount of normal tissue would have to be irradiated to sterilize the tumor, but yet too large or invasive to be removed completely surgically. It is the physical characteristics of a tumor that determine, in most cases, the most suitable modality to be used in therapy.
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SELECTION OF THE RADIOTHERAPY PROTOCOL Once it has been decided that a tumor is to be irradiated, one of two approaches is usually taken in veterinary medicine-teletherapy or brachytherapy.
Teletherapy Teletherapy implies that the source of the radiation is at some distance from the body. Therapeutic x-ray machines and the radioactive compounds 6 °Co and 137 Cs are the most common sources of radiation used for teletherapy in veterinary medicine. Most tumors that are treated with radiation are treated with teletherapy because at the time they are presented for therapy they are usually too large to be treated with brachytherapy. In teletherapy the beam of radiation is directed upon an area of the body that encompasses the tumor and some margin of apparently normal tissue. The choice of the size of the margin of normal tissue is a value judgment made by the radiotherapist and frequently dictates the difference between success, local recurrence, and necrosis of normal tissue. The radiation dose is not given in one large fraction but in several smaller fractions spread out over a given time interval. The reason for this is to allow the normal tissue to repair some of the radiation damage and to repopulate the area as discussed previously. Also, during the intertreatment interval, some of the hypoxic tumor cells may become oxygenated as the aerobic cells are killed and therefore become more radiosensitive. The scheduling and magnitude of the fractions are empirical. In human radiotherapy many tumors are treated with fractions of 200 rads given five times per week on a Monday, Tuesday, W ednesday, Thursday, Friday schedule for six weeks for a total dose of 6000 rads. This is impractical in veterinary radiotherapy due to the long total treatment time and the necessity of sedating and/or anesthetizing the animal five times per week. Most veterinary radiotherapists use larger doses per fraction (400 to 500 rads) given three times per week on a Monday, Wednesday, Friday schedule for two or three weeks for total doses of 3000 to 5000 rads. The combination of teletherapy with surgery is one that is frequently overlooked. This combination has many potential uses especially when one is certain or even suspects that all of the malignancy was not removed at surgery. This is the time to act, not after recurrence is obvious. There is no place for procrastination in oncology.
Brachytherapy Brachytherapy is radiotherapy with sealed radioactive sources in which the source is placed upon or into the tumor. 6 °Co and 137 Cs needles, either inserted into the lesion or placed on the surface as packs, 222 Rn seeds inserted into the lesion, and 90 Sr used in a surface applica-
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tor are the types of brachytherapy used most frequently in veterinary medicine. Brachytherapy is most useful in tumors of large animals, where 9 or 10 fractionated teletherapy treatments are impossible, and in small tumors which cannot be conveniently treated with teletherapy, such as tonsillar carcinoma. Brachytherapy is also useful in tumors, such as corneal squamous cell carcinomas, which cannot be treated with teletherapy without damaging vital normal structures such as the lens. There are certain advantages and disadvantages ofbrachytherapy when compared with teletherapy. 7 Advantages. (1) The tumor dose is much higher- greater than 10000 rads compared with less than 5000 rads for teletherapy. (2) Tumor tissue receives a higher dose than normal tissue. (3) In-hospital treatment times are short. Disadvantages. (1) Interstitial implantation of the sources requires a minor surgical procedure. (2) Trauma to the tumor may produce an undesirable shower of tumor cells into the blood. (3) Interstitial implantation poses a radiation exposure problem to the operator as well as to the patient and everyone in contact with it.
CASE EXAMPLES The following cases illustrate Lhe principles and application of radiation therapy. Case 1 A five year old male domestic short hair cat was presented with an 11 month history of a progressive ulcerative lesion of both nares (Fig. 1A). Several veterinarians previously had treated the undiagnosed lesion with cautery, antibiotics, and corticosteroids with no improvement. The lesion bled easily when touched. To obtain a diagnosis, a direct smear was made of the lesion and submitted for cytology. The presence of class IV cells was cytological evidence of carcinoma. There was no clinical or radiographic evidence of metastasis. The tumor did not locally involve bone. The tumor was considered to be inoperable and was treated with x-ray teletherapy. Five treatments of 500 rad fractions were administered for a total tumor surface dose of 2500 rads. The carcinoma had decreased in size by one half when therapy was completed 12 days later. Four years later, the cat is healthy with no tumor recurrence (Fig. 1B).
Case 2 A six year old male German shepherd dog was presented with a 1 X2 X21h em oral fibrosarcoma of the gingiva adjacent to the left upper canine tooth (Fig. 2A). The tumor had been surgically excised one month previously. The fibrosarcoma recurrence was considered to be inoperable. As the dog was vicious and difficult to handle, interstitial brachytherapy was chosen as the best treatment to maximally irradiate the tumor as it would require only one anesthetic episode and short hospitalization. Radon seeds (7 mCi) were placed symmetrically within the tumor so that following complete decay at 30 days, a 4000
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Figure l. A, Case l. Five year old male domestic sh ort-hair car. with a squamous cell carcinoma of the nares prior to radia tion therapy. B , Four years later there is no evidence of tumor recurren ce. T he n ares are deformed .
Figure 2.
A, Case 2. Oral fibrosarcoma of a 6 year old Germ an she phe rd dog prior
to brach ytherapy with radon. B , Radiogr aph d emonstrating the position of the radon
seeds implanted within the fibrosarcoma. C, Thirty-fi ve days following radon interstitial brachytherapy the tumor h as sloug hed completely. D, A fi stulous tract d eveloped 11 months following irradiation. There was no clinical or h istological evidence of fibrosarcom a recurrence.
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rad dose would be delivered to the tumor (Fig. 2B ). Within six days the neoplasm was gray in color (representing necrosis). Thirty-five days after implantation, the tumor had sloughed completel y with no clinical evidence of fibrosarcoma (Fig. 2C). The dog did well with no tumor recurrence for ll mo nths when a fistulous tract of minor clinical significance developed over the lateral maxilla secondary to the previous irradiation (Fig. 2D). The fistula did not appear to cause pain or affect the dog. The dog became more difficult for the owner to handle and the owner requested the dog be euthanized. On histological examination, there was no evidence of tumor, only the fistulous tract.
Case 3 A three year old female Irish wolfhound with a three week history of a mass on the rostral right mandible was examined (Fig. 3). The mass had doubled in size during the previous week. There was no clinical or radiographic evidence of metastatic disease. The dog was anesthetized, occlusal radiographs of the mandible were made, and as much of the lesion as possible was removed for biopsy. Radiographically, there was lysis of the right rostral mandible adjacent to the third incisor and canine tooth. These changes were most characteristic of a malignant soft tissue tumor invading the adjacent bone. Histologically, the mass was diagnosed as a squamous cell carcinoma infiltrating bone. Additional surgery was not indicated, and x-ray teletherapy was given. A total dose of 2000 rads in four equal fractions was administered on alternate days. Two months following treatment the tumor h ad r egr essed slowl y in size to approximately two-thirds the original volume. The dog was examined clinically and radiographically at regular intervals following irradiation. Twenty-one months after irradiation, the mass had not changed in size or appearance, but there was radiographic evidence of additional bone lysis indicating tumor progression. An additional 1000 rads of x-ray teletherapy was administered. Clinically, at 21/2 years following initial irradiation and 9 months following the second course of radiation, the mass remains unchan ged with sclerotic bone r e placing the previous lytic a rea in the mandible. For acad emic interest, the lesion site was rebiopsied. No histological evidence of malignant disease was seen.
Figure 3. Case 3. l'reir r adiation appearance of an o ral squamous cell carcinoma in a 3 year old Irish woltlw und .
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Figure 4. A, Case 4. Preirradiation appearance of an epide rmoid carcinoma of the left lateral maxilla in a 12 year old German shepherd clog. B, The epidermoid carcinoma regressed to approximately one-half its original volume within eight days of irradiation with 4000 rads. C, There is no evidence of tumor six months following irradiation. T he hair has regrown 14 months later, but is white secondary to irradiation.
Case 4 A 12 year old male German shepherd dog was presented with a two month history of a rapidly growing cutaneous mass on the left lateral maxillary region (Fig. 4A). The diagnosis following biopsy was sebaceous adenocarcinoma. There was no clinical or radiographic evidence of metastatic disease. Four equal fractions of 1000 rads combined with a radioprotective drug* were given on alternate days for a total of 4000 rads to the 3 by 3 em tumor surface in eight days. During irradiation, the tumor had regressed to approximately half of its original volume (Fig. 4B) with complete regression 43 days following irradiation (Fig. 4C). The dog remains normal with no evidence of tumor recurrence 14 months later. Hair has now regrown at the treated site but is white secondary to the irradiation .
Case 5 A seven year old female Tibetan te rrier was presented with a rostral oral mandibular mass located between the canine teeth (Fig. 5A). The mass was first observed four months previously by the owner. The mass was progressively enlarging. There was no clinical or radiographic evidence of metastasis. The diagnosis following biopsy was ameloblastoma. Radiographically, lysis of the mandible was observed adjacent to the symphysis and incisor teeth (Fig. 5B). Irradiation with x-ray teletherapy was considered the best method of treatment. Six fractions of 500 rads each were administered on alternate d ays for a total tumor dose of 3000 rads. Three different portals of treatment we re used: *WR 2721. Funds for study provided by ERT A and East T e nnessee Cancer Re;earch Center.
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Figure 5. A, Case 5. Preirradiation appearance of a mandibular ameloblastoma in a 7 year old female Tibetan terrier. A biopsy was made immediately prior to pho tograph. B, A poorly d e mar cated lytic lesion was seen radiographically adjacent to the mand ibular symphysis and incisor teeth.
left lateral, right lateral, and ventrodorsal. The tumor regressed completely within one month following irradiation. No clinical evidence of tumor recurrence was observed for four years (Fig. 6A). Permanent epilation resulted from the irradia tion (Fig. 6B). Four years following this treatment, there was clinical, radiographic, and histological evidence of tumor recurrence. An additional 2000 rads of x-ray teletherapy was administered. Unfortunatel y, the dog was accidently killed at home one month following the second treatment and no necropsy was performed.
Figure 6. A, Case 5. T he re was no clinical evid ence of tumor recurrence rour years following irradiation. B, Per manent e pilation resulted from the irrad iation. An indentation on the ventr al mandible following tumor regression can be seen.
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Figure 7. Case 6. Complete lysis of both rostral mandibles from a squamous cell carcinoma. Treatment of a lesion of this severity with radiation th era py is inappropriate.
Case 6 A nine year old spayed female mm1ature poodle was presented with an oral mass involving the rostral mandible. The mass had been surgically removed three times previously with subsequent recurrence each time. The histological diagnosis was squamous cell carcinoma. When the tumor recurred following the third surgery, the dog was referred for radiation therapy. Occlusal radiographs were made of the lesion site as part of the routine patient and tumor evaluation. Radiographically, the lesion was extensive with complete lysis of both rostral mandibles (Fig. 7) . Radiation therapy was considered inapproapriate at this late . clinical stage. If the tumor had been irradiated and had responded, the dog would have had no functional lower jaw, an unacceptable sequela. Veterinarians must consider radiation therapy as an appropriate
mode of treatment early in the disease process and not as a "last ditch " effort.
TUMOR RESPONSE A definitive diagnosis and staging of a malignant lesion are essential before deciding on the treatment modality. If radiation therapy is to be given, the animal should have a predicted reasonable life expectancy and no other concurrent serious medical or surgical disease. Prior to irradiation of a diagnosed malignant lesion, as much of the neoplasm as possible should be removed surgically. The smaller the tumor volume, the better the potential effect of irradiation. Even
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though aggressive radiotherapy is best, some neoplasms can be treated palliatively with less than curative doses to produce tumor regression, stages of tumor growth, or relief of pain enabling the animal to be more comfortable for a short period of time. The rate of tumor regression during or following radiation therapy has not proved helpful prognostically. For example, a neoplasm that regresses completely during irradiation may recur just as rapidly several weeks later. Conversely, a neoplasm may not change in size following irradiation and remain unchanged for years, representing a cure. There is a paucity of published data concerning the effectiveness of radiotherapy in treating neoplasms in the dog and cat; therefore the probability of cure cannot be stated precisely. At present, most tumors which have been treated with irradiation have been either difficult or impossible to remove surgically or have recurred following previous surgery. Histological and clinical staging of tumors and radiation therapy protocols have not been uniform. Clinically, it is obvious that cure rates differ for the individual tumor based on numerous factors such as patient health, location, and clinical and histological staging of the tumor. The following tumors appear to be the most radioresponsive: perianal adenoma, perianal adenocarcinoma, squamous cell carcinoma, adenocarcinoma, ameloblastoma, mast cell sarcoma, and transmissible venereal tumor. Fibrosarcoma and malignant melanoma are less radioresponsive but may be effictively controlled for several to many months. Carcinomas in general are more radioresponsive than are sarcomas. It is our experience that following radiotherapy in dogs and cats, one year survival data without clinical evidence of tumor recurrence is approximately 50 per cent for squamous cell carcinoma, perianal adenomas, and perianal adenocarcinomas, and approximately 40 per cent for mast cell tumors. Postoperative irradiation of nasal adenocarcinoma and squamous cell carcinoma in dogs has been successful in controlling most tumors and extending the animal's life an additional 5 to 14 months longer than is reported when only surgery is done. Approximately 50 per cent of the fibrosarcomas can be controlled for 6 to 14 months. Of six oral malignant melanomas in dogs treated after recurrence following surgery, irradiation successfully produced regression and control for as long as 18 months in one dog and three years in another dog. A recently completed study reports the percentage control of 241 canine tumors for at least one year without tumor recurrence following radiation therapy doses of 3000 rads and higher. 4 The control was 4 7 per cent for perianal tumors, 52 per cent for mast cell tumors and squamous cell carcinomas, 10 per cent for adenocarcinomas, and 27 per cent for fibrosarcomas.
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FOLLOW-UP When one looks critically at the medical literature, it is not difficult to find numerous articles reporting on the efficacy of accepted modes of treating human cancer as well as suggestions for new ways in which to handle certain aspects of this dread conglomerate of diseases. These reports can be found in both general medical journals and specialty journals. It is apparent in looking critically at the medical literature that articles reporting on the efficacy of various modes of treatment of animal cancer are limited. The reason for this discrepancy is related to a number of factors. First, cancer is not a pleasant entity to deal with and therefore has not been attacked enthusiastically by the majority of veterinarians. Second, surgical removal of the tumor has remained the principal method of dealing with animal cancer. Although this same practice occurred in human medicine, physicians have recorded data relative to tumor type and success rate while too often the veterinarian has failed to accumulate data concerning the outcome of the patient. Even veterinarians who have kept complete organized records have apparently hesitated to make this information available through publication. Finally, the fact that cancer can be cured, or at least put into longterm remission in a significant number of instances, is not fully realized and probably too often our option to perform active euthanasia is exercised prematurely. Why is it important to record data on the efficacy of cancer therapy in animals? A number of reasons should stimulate us to take an organized approach in record keeping and data retrieval. First, it would provide a service of higher quality to our clients. Companion animals develop cancer at an incidence of approximately 381 new cases per l 00,000 dogs per year and 156 new cases per 100,000 cats per year. 7 By the time animals do develop cancer, they are generally elderly and have become an integral part of the family. Owners of these animals usually are very willing to support an attempt to save or prolong the life rather than have euthanasia performed if such an option is offered to them. At present, many such people expect top quality medical care for their pets. If no data exist on the efficacy of a particular type of therapy, there can be no way of determining how to modify the treatment protocol or whether a modification which has been instituted is beneficial or detrimental. Another reason it is important to accumulate data relative to cancer therapy is that the information may be helpful to physician colleagues in terms of modifying their protocols for the treatment of cancer in man. The information that we compile is of great potential value. There is no justification for the utilization of a procedure without some knowledge, or at least a plan to accumulate knowledge, regarding its efficacy. Every veterinarian treating cancer patients should strive to
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obtain complete follow-up information so that the treatment protocol utilized can be evaluated. Logistically, this can be accomplished either by a phone call to local clients or a questionnaire mailed to more distant clients. At the University of Pennsylvania, each client whose animal receives radiation therapy is sent a personal letter containing a selfaddressed stamped questionnaire inquiring about a number of aspects of the radiation treatment. The letter is sent to each client every six months until contact is lost or the final status of the animal is known. Client response to this form of questionnaire is excellent. A certain amount of effort and expense is associated with this type of data retrieval system; however, these factors are insignificant when compared with the actual value of the information obtained. · The importance of following up each case treated cannot be emphasized strongly enough. Compilation and reporting of data concerning the efficacy of cancer treatment must be done if therapy of cancer m animals is to be accomplished in a scientifically acceptable fashion.
NEW RADIOTHERAPY MODALITIES As the art and science of human radiotherapy progress, much attention is being given to mew modalities in the hope of increasing the existing cure rates. Data obtained from using these new modalities on spontaneous tumors in domestic animals would be an extremely valuable contribution to medical science. The three modalities receiving the most attention at the present time are neutron radiotherapy, 7T-meson radiotherapy, and hyperthermia. Neutron Radiotherapy
Neutrons are uncharged particles with a mass approximately 200 times greater than an electron. Neutrons may be well suited as a radiotherapy modality for two reasons.!! (l) They kill hypoxic cells almost as efficiently as they kill oxygenated tumor cells. This is not the case for xrays or gamma rays. Hypoxic cells require two to three times the amount of x-irradiation or gamma irradiation to be killed when compared with oxygenated cells. Hypoxic tumor cells may become reoxygenated and lead to recurrence of the tumor; therefore neutrons are more efficient in eliminating the hypoxic tumor cells which may lead to tumor regrowth. (2) Neutrons produce less radiation damage which is capable of being repaired in the intertreatment interval; therefore the net effect of fractionation schemes of neutron irradiation is less likely to vary as a result of the frequency of the fractions when compared with xirradiation or gamma irradiation.
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7T-Meson Radiotherapy Negative 1T mesons are negatively charged particles having a mass 273 times greater than the mass of an electron. The Los Alamos Scientific Laboratory of the University of California at Los Alamos, New Mexico is a recently completed facility. dedicated entirely to studying the physical, biological, and medical applications of 1r-mesons. Negative 1T mesons have attracted considerable interest as a radiotherapy modality because of their property of producing a greater deposition of energy at a certain depth into the body rather than at or near the surface as is the case with x-irradiation or gamma irradiation. This naturally would be desirable in cases in which the tumor was not located at the surface of the body.
Hyperthermia Hyperthermia implies raiSing the temperature of tissues and has been advocated as a useful cancer therapy modality both alone and in combination with ionizing radiation for the following reasons :9 (l) heat suppresses the ability of cells to repair radiation damage; (2) heat enhances the expression of lethal radiation damage; (3) tumor cells may be more heat-sensitive than are normal cells; and (4) hypoxic cells are more heat-sensitive than are aerobic cells.
REFERENCES I. Biery, D. N.: Radiation therapy in dermatology. In Kirk, R. W. (ed.): Current Veterinary Therapy VI. Philadelphia, W. B. Saunders Co., 1977. 2. Dorn, C. R., Taylor, D. 0. N., Schneider, R., eta!.: Survey of animal neoplasms in Alameda and Contra Costa Counties, California. II. Cancer morbidity in dogs and cats from Alameda County. J. Nat. Cancer Inst., 40:307-318, 1968. 3. (~illette, E. L.: Indications and selection of patients for radiation therapy. VET. Cux. NORTH AM., 4:889-896, 1975. -!. Gillette, E. L.: Radiation oncology. In Kirk, R. W. (ed): Current Veterinary Therapy VI. Philadelphia, W. B. Saunders Co., 1977. 5. Gilette, E. L.: Veterinary radiotherapy. J.A.V.M.A., 157:1707-1712, 1972. 6. Hall, E . .J.: Radiobiology for the Radiologist. Hagerstown, Md., Harper and Row, Inc., 1973. 7. Hilaris, B. S.: A Manual for Brachytherapy. New York, Memorial Sloan Kettering Cancer Center. 8. Silver, I. A.: Use of radiotherapy for the treatment of malignant neoplasms. J. Small Anim. Pract., 13:351-358, 1972. 9. Thrall, D. E., Gerweck, L. E., Gillette, E. L., eta!.: Response of cells in vitro and tissues in vivo to hyperthermia and x-irradiation. Adv. Radiation Bioi., 6:211-227, 1976.
Department of Anatomy and Radiology College of Veterinary Medicine University of Georgia Athens, Georgia 30602
Principles and Application of Radiation Therapy
Donald E. Thrall, D.V.M., Ph.D.,* and Darryl N. Biery, D.V.M.t
Radiotherapy in veterinary medicine is not enjoying the same degree of popularity that it is in human medicine. This is due to three factors: economics, lack of a unified organized approach to the problem of cancer in animals, and a general lack of knowledge regarding the usefulness of radiotherapy in veterinary medicine.
Economics No one can argue the importance of economics relative to the practice of certain aspects of veterinary medicine. This is particularly true regarding radiotherapy which necessitates costly equipment and the charge to the client routinely involves many hundreds of dollars. ~evertheless, many clients are willing to tolerate the expense and opt for radiotherapy. Therefore, the teaching centers of veterinary medicine have some obligation to the public to provide a competent radiotherapy service and practitioners of veterinary medicine have an obligation to make the owner of an animal with cancer aware of radiotherapy.
Lack of an Organized Approach Ten years ago there was no question that an organized approach to the management of animal cancer did not exist. This is not true today as evidenced by the recent formation of the Veterinary Cancer Society and this symposium on veterinary clinical oncology. The structure of an organized approach to the problem of animal cancer is covered elsewhere in this symposium; however, it is important here to *.\ssistant Professor of Radiology, School of Veterinary Medicine and School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania "'.\ssociate Professor and Chief, Section of Radiology, School of Veterinary Medicine, and Associate Professor of Radiological Science, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania l"eterinary Clinics of North America- Vol. 7, No. 1, February 1977
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stress the value of the cooperation of the private practitioner regarding the success of such a program.
Lack of Knowledge Regarding Usefulness of Radiotherapy It is little surprise that many practicing veterinarians have minimal appreciation for the usefulness of radiotherapy in the management of the cancer patient. This stems from the fact that for many years radiotherapy was not stressed by the veterinary schools themselves. Hopefully this paper will enhance the general appreciation of the usefulness of radiotherapy in the management of the cancer patient.
PRINCIPLES There is nothing mystical about the ability of or method by which radiation kills cells. All radiations used to treat cancer produce ions in the tissue in which they interact and thus are termed ionizing radiation. An ion is simply an atom with an excess of deficiency of electrons. Ionizing radiation produces ions by removing electrons from atoms, and is either directly or indirectly ionizing. Directly ionizing radiation is particulate and charged (e.g., electrons, alpha particles, and ?T-mesons) and produces direct atomic disruption in the tissue through which it passes. Indirectly ionizing radiation (e.g., x-rays, gamma rays, and neutrons) does not produce the majority of atomic disruption itself but does so via high speed charged particles to which it transfers energy in the body. In veterinary medicine most radiotherapy utilizes x-rays and gamma rays. Both x-rays and gamma rays are electromagnetic radiation with wave lengths less than 1o-s em. Radio waves, radar waves, and visible light waves are also electromagnetic radiation but are not capable of producing ions due to their longer wave length and lower energy. The physical and biologic properties of x-rays and gamma rays are essentially identical. The x and gamma simply refer to the site of production of the radiation. X-rays are produced outside the nucleus of an atom by an interaction involving a high speed electron and gamma rays are produced in the nucleus of an atom and represent a method by which an unstable nucleus may rid itself of excess energy. The actual amount of physical damage introduced into tissue by therapeutic doses of ionizing radiation is negligible. For example, the energy deposited in tissue by 1000 rads ( 1 rad equals the absorption of 1000 ergs of energy per gm of tissue) raises the temperature of the tissue only about 0.001° C. This dose of radiation, however, will easily kill the largest man if administered to his entire body. Therefore, there must be some biologic amplification which enhances the initial damage produced. At this time most radiobiologists favor the theory that the lethal lesion in the cell is disruption of nuclear DNA. This can occur
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when relatively little energy is deposited in the DNA and has the potential for becoming lethal to the cell when the cell tries to divide. Thus the biologic amplification of the initial energy deposition is mediated through damage to DNA and culminates in cell death when the cell attempts to divide. Radiation kills both normal and neoplastic cells to about the same extent. In most cases tumor cells are not more sensitive than normal cells to the killing effects of radiation. This poses no problem in terms of killing a tumor with radiation. Any tumor can be killed with radiation provided the dose is high enough. The problem this lack of differential sensitivity does impose is how to selectively kill a tumor with radiation while sparing sufficient normal tissue to repair the defect produced by killing the tumor. Two approaches to solving this problem are dividing the total dose into smaller fractions separated by a certain period of time (i.e., fractionation) and implanting radioactive material directly into the tumor. Two factors which have some influence on the inherent radiosensitivity of cells are the position of the cell in the cell division cycle and the oxygenation level of the cell. In terms of the cell division cycle, the most radiosensitive phase is during mitosis and the most radioresistant phase is late during the period of DNA synthesis. As of this date, no one has been able to put this cell-cycle related fluctuation of radiosensitivity to therapeutic use. On the other hand, differences in oxygen tension may be very important in determining whether a tumor can be cured with radiation. Viable hypoxic cells require two to three times more radiation to be killed than do aerobic cells. Hypoxic viable cells do exist in spontaneous tumors of animals. It is these cells that may survive a course of radiation and lead to recurrence of the tumor. Fractionation may lead to destruction of the hypoxic cell compartment by allowing the hypoxic cells to become reoxygenated in the intertreatment interval and therefore more sensitive to the killing effects of the radiation given during the next fraction. Contrary to popular belief, many types of tumor cells are actually dividing more slowly than are the surrounding normal tissues. Or, on the other hand, if the tumor cell population is dividing more rapidly than the normal cell population before irradiation, the situation may reverse itself after irradiation due to homeostatic shortening of the division rate of the normal cell production. Both situations are conducive to the success of fractionating the x-ray dose because in the intertreatment interval the more rapidly dividing normal tissue cells are capable of increasing their total cell number relative to the neoplastic cell number. The alternative solution to the problem of similar radiosensitivity of normal and tumor cells is the implantation of radioactive substances into the tumor. This technique, of course, would deposit a larger radiation dose into the tumor relative to the normal tissue and would favor sterilization of the tumor.
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As implied in the above discussion, the single limiting factor regarding the probability of satisfactory tumor cure by radiotherapy is the amount of radiation that can be tolerated by the surrounding normal tissue.
INDICATIONS AND SELECTION OF PATIENTS Radiotherapy is looked upon by some as a "last ditch" effort to be reserved for use in cases in which all else has failed. Previous reports of cure rates of animal tumors treated with radiation indicate that this should not be the case. L 3-5 • 8 On the other hand, radiotherapy is not a panacea for cancer. Radiotherapy occupies a distinct and well defined niche in the armamentarium of the oncologist. The first step in determining the applicability of radiotherapy in an animal with cancer is the performance of a thorough physical examination. Particular attention must be paid to the presence or absence of metastatic disease. To do this accurately one must possess an explicit knowledge of the mechanisms of the spread of disease. All too often regional nodes are overlooked. Generally speaking, the animal should be in relatively good health before any treatment is initiated. After the general evaluation is complete, the tumor should be evaluated primarily for its size, location, and invasiveness. A biopsy must be obtained to document that one is in fact dealing with a malignancy, to gain insight as to how the tumor is likely to metastasize, and for prognosis. Usually the tumor cell type in itself has little to do with the modality chosen to treat the tumor. After a definitive diagnosis of malignancy is made the next decision is to choose between aggressive therapy and euthanasia. These are the only two choices that warrant consideration since any therapy that is instituted should be aggressive. This decision should be made by the client after all options and pertinent information have been made known by the veterinarian. Not every tumor is amenable to radiotherapy. In general, widely disseminated neoplasia, such as lymphosarcoma, granulocytic leukemia, and metastatic disease, can only be treated chemotherapeutically. Tumors that are well localized and have not extensively invaded adjacent structures are best treated surgically. Tumors that are well localized and relatively superficially located but are locally invasive are best treated by radiotherapy. Obviously all tumors do not fall into one of the above three categories. In these cases two, or even three, of the above modalities can be combined for optimal management of the tumor. In general, radiotherapy is reserved as the primary modality for tumors not so large than an excess amount of normal tissue would have to be irradiated to sterilize the tumor, but yet too large or invasive to be removed completely surgically. It is the physical characteristics of a tumor that determine, in most cases, the most suitable modality to be used in therapy.
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SELECTION OF THE RADIOTHERAPY PROTOCOL Once it has been decided that a tumor is to be irradiated, one of two approaches is usually taken in veterinary medicine-teletherapy or brachytherapy.
Teletherapy Teletherapy implies that the source of the radiation is at some distance from the body. Therapeutic x-ray machines and the radioactive compounds 6 °Co and 137 Cs are the most common sources of radiation used for teletherapy in veterinary medicine. Most tumors that are treated with radiation are treated with teletherapy because at the time they are presented for therapy they are usually too large to be treated with brachytherapy. In teletherapy the beam of radiation is directed upon an area of the body that encompasses the tumor and some margin of apparently normal tissue. The choice of the size of the margin of normal tissue is a value judgment made by the radiotherapist and frequently dictates the difference between success, local recurrence, and necrosis of normal tissue. The radiation dose is not given in one large fraction but in several smaller fractions spread out over a given time interval. The reason for this is to allow the normal tissue to repair some of the radiation damage and to repopulate the area as discussed previously. Also, during the intertreatment interval, some of the hypoxic tumor cells may become oxygenated as the aerobic cells are killed and therefore become more radiosensitive. The scheduling and magnitude of the fractions are empirical. In human radiotherapy many tumors are treated with fractions of 200 rads given five times per week on a Monday, Tuesday, W ednesday, Thursday, Friday schedule for six weeks for a total dose of 6000 rads. This is impractical in veterinary radiotherapy due to the long total treatment time and the necessity of sedating and/or anesthetizing the animal five times per week. Most veterinary radiotherapists use larger doses per fraction (400 to 500 rads) given three times per week on a Monday, Wednesday, Friday schedule for two or three weeks for total doses of 3000 to 5000 rads. The combination of teletherapy with surgery is one that is frequently overlooked. This combination has many potential uses especially when one is certain or even suspects that all of the malignancy was not removed at surgery. This is the time to act, not after recurrence is obvious. There is no place for procrastination in oncology.
Brachytherapy Brachytherapy is radiotherapy with sealed radioactive sources in which the source is placed upon or into the tumor. 6 °Co and 137 Cs needles, either inserted into the lesion or placed on the surface as packs, 222 Rn seeds inserted into the lesion, and 90 Sr used in a surface applica-
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tor are the types of brachytherapy used most frequently in veterinary medicine. Brachytherapy is most useful in tumors of large animals, where 9 or 10 fractionated teletherapy treatments are impossible, and in small tumors which cannot be conveniently treated with teletherapy, such as tonsillar carcinoma. Brachytherapy is also useful in tumors, such as corneal squamous cell carcinomas, which cannot be treated with teletherapy without damaging vital normal structures such as the lens. There are certain advantages and disadvantages ofbrachytherapy when compared with teletherapy. 7 Advantages. (1) The tumor dose is much higher- greater than 10000 rads compared with less than 5000 rads for teletherapy. (2) Tumor tissue receives a higher dose than normal tissue. (3) In-hospital treatment times are short. Disadvantages. (1) Interstitial implantation of the sources requires a minor surgical procedure. (2) Trauma to the tumor may produce an undesirable shower of tumor cells into the blood. (3) Interstitial implantation poses a radiation exposure problem to the operator as well as to the patient and everyone in contact with it.
CASE EXAMPLES The following cases illustrate Lhe principles and application of radiation therapy. Case 1 A five year old male domestic short hair cat was presented with an 11 month history of a progressive ulcerative lesion of both nares (Fig. 1A). Several veterinarians previously had treated the undiagnosed lesion with cautery, antibiotics, and corticosteroids with no improvement. The lesion bled easily when touched. To obtain a diagnosis, a direct smear was made of the lesion and submitted for cytology. The presence of class IV cells was cytological evidence of carcinoma. There was no clinical or radiographic evidence of metastasis. The tumor did not locally involve bone. The tumor was considered to be inoperable and was treated with x-ray teletherapy. Five treatments of 500 rad fractions were administered for a total tumor surface dose of 2500 rads. The carcinoma had decreased in size by one half when therapy was completed 12 days later. Four years later, the cat is healthy with no tumor recurrence (Fig. 1B).
Case 2 A six year old male German shepherd dog was presented with a 1 X2 X21h em oral fibrosarcoma of the gingiva adjacent to the left upper canine tooth (Fig. 2A). The tumor had been surgically excised one month previously. The fibrosarcoma recurrence was considered to be inoperable. As the dog was vicious and difficult to handle, interstitial brachytherapy was chosen as the best treatment to maximally irradiate the tumor as it would require only one anesthetic episode and short hospitalization. Radon seeds (7 mCi) were placed symmetrically within the tumor so that following complete decay at 30 days, a 4000
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Figure l. A, Case l. Five year old male domestic sh ort-hair car. with a squamous cell carcinoma of the nares prior to radia tion therapy. B , Four years later there is no evidence of tumor recurren ce. T he n ares are deformed .
Figure 2.
A, Case 2. Oral fibrosarcoma of a 6 year old Germ an she phe rd dog prior
to brach ytherapy with radon. B , Radiogr aph d emonstrating the position of the radon
seeds implanted within the fibrosarcoma. C, Thirty-fi ve days following radon interstitial brachytherapy the tumor h as sloug hed completely. D, A fi stulous tract d eveloped 11 months following irradiation. There was no clinical or h istological evidence of fibrosarcom a recurrence.
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rad dose would be delivered to the tumor (Fig. 2B ). Within six days the neoplasm was gray in color (representing necrosis). Thirty-five days after implantation, the tumor had sloughed completel y with no clinical evidence of fibrosarcoma (Fig. 2C). The dog did well with no tumor recurrence for ll mo nths when a fistulous tract of minor clinical significance developed over the lateral maxilla secondary to the previous irradiation (Fig. 2D). The fistula did not appear to cause pain or affect the dog. The dog became more difficult for the owner to handle and the owner requested the dog be euthanized. On histological examination, there was no evidence of tumor, only the fistulous tract.
Case 3 A three year old female Irish wolfhound with a three week history of a mass on the rostral right mandible was examined (Fig. 3). The mass had doubled in size during the previous week. There was no clinical or radiographic evidence of metastatic disease. The dog was anesthetized, occlusal radiographs of the mandible were made, and as much of the lesion as possible was removed for biopsy. Radiographically, there was lysis of the right rostral mandible adjacent to the third incisor and canine tooth. These changes were most characteristic of a malignant soft tissue tumor invading the adjacent bone. Histologically, the mass was diagnosed as a squamous cell carcinoma infiltrating bone. Additional surgery was not indicated, and x-ray teletherapy was given. A total dose of 2000 rads in four equal fractions was administered on alternate days. Two months following treatment the tumor h ad r egr essed slowl y in size to approximately two-thirds the original volume. The dog was examined clinically and radiographically at regular intervals following irradiation. Twenty-one months after irradiation, the mass had not changed in size or appearance, but there was radiographic evidence of additional bone lysis indicating tumor progression. An additional 1000 rads of x-ray teletherapy was administered. Clinically, at 21/2 years following initial irradiation and 9 months following the second course of radiation, the mass remains unchan ged with sclerotic bone r e placing the previous lytic a rea in the mandible. For acad emic interest, the lesion site was rebiopsied. No histological evidence of malignant disease was seen.
Figure 3. Case 3. l'reir r adiation appearance of an o ral squamous cell carcinoma in a 3 year old Irish woltlw und .
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Figure 4. A, Case 4. Preirradiation appearance of an epide rmoid carcinoma of the left lateral maxilla in a 12 year old German shepherd clog. B, The epidermoid carcinoma regressed to approximately one-half its original volume within eight days of irradiation with 4000 rads. C, There is no evidence of tumor six months following irradiation. T he hair has regrown 14 months later, but is white secondary to irradiation.
Case 4 A 12 year old male German shepherd dog was presented with a two month history of a rapidly growing cutaneous mass on the left lateral maxillary region (Fig. 4A). The diagnosis following biopsy was sebaceous adenocarcinoma. There was no clinical or radiographic evidence of metastatic disease. Four equal fractions of 1000 rads combined with a radioprotective drug* were given on alternate days for a total of 4000 rads to the 3 by 3 em tumor surface in eight days. During irradiation, the tumor had regressed to approximately half of its original volume (Fig. 4B) with complete regression 43 days following irradiation (Fig. 4C). The dog remains normal with no evidence of tumor recurrence 14 months later. Hair has now regrown at the treated site but is white secondary to the irradiation .
Case 5 A seven year old female Tibetan te rrier was presented with a rostral oral mandibular mass located between the canine teeth (Fig. 5A). The mass was first observed four months previously by the owner. The mass was progressively enlarging. There was no clinical or radiographic evidence of metastasis. The diagnosis following biopsy was ameloblastoma. Radiographically, lysis of the mandible was observed adjacent to the symphysis and incisor teeth (Fig. 5B). Irradiation with x-ray teletherapy was considered the best method of treatment. Six fractions of 500 rads each were administered on alternate d ays for a total tumor dose of 3000 rads. Three different portals of treatment we re used: *WR 2721. Funds for study provided by ERT A and East T e nnessee Cancer Re;earch Center.
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Figure 5. A, Case 5. Preirradiation appearance of a mandibular ameloblastoma in a 7 year old female Tibetan terrier. A biopsy was made immediately prior to pho tograph. B, A poorly d e mar cated lytic lesion was seen radiographically adjacent to the mand ibular symphysis and incisor teeth.
left lateral, right lateral, and ventrodorsal. The tumor regressed completely within one month following irradiation. No clinical evidence of tumor recurrence was observed for four years (Fig. 6A). Permanent epilation resulted from the irradia tion (Fig. 6B). Four years following this treatment, there was clinical, radiographic, and histological evidence of tumor recurrence. An additional 2000 rads of x-ray teletherapy was administered. Unfortunatel y, the dog was accidently killed at home one month following the second treatment and no necropsy was performed.
Figure 6. A, Case 5. T he re was no clinical evid ence of tumor recurrence rour years following irradiation. B, Per manent e pilation resulted from the irrad iation. An indentation on the ventr al mandible following tumor regression can be seen.
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Figure 7. Case 6. Complete lysis of both rostral mandibles from a squamous cell carcinoma. Treatment of a lesion of this severity with radiation th era py is inappropriate.
Case 6 A nine year old spayed female mm1ature poodle was presented with an oral mass involving the rostral mandible. The mass had been surgically removed three times previously with subsequent recurrence each time. The histological diagnosis was squamous cell carcinoma. When the tumor recurred following the third surgery, the dog was referred for radiation therapy. Occlusal radiographs were made of the lesion site as part of the routine patient and tumor evaluation. Radiographically, the lesion was extensive with complete lysis of both rostral mandibles (Fig. 7) . Radiation therapy was considered inapproapriate at this late . clinical stage. If the tumor had been irradiated and had responded, the dog would have had no functional lower jaw, an unacceptable sequela. Veterinarians must consider radiation therapy as an appropriate
mode of treatment early in the disease process and not as a "last ditch " effort.
TUMOR RESPONSE A definitive diagnosis and staging of a malignant lesion are essential before deciding on the treatment modality. If radiation therapy is to be given, the animal should have a predicted reasonable life expectancy and no other concurrent serious medical or surgical disease. Prior to irradiation of a diagnosed malignant lesion, as much of the neoplasm as possible should be removed surgically. The smaller the tumor volume, the better the potential effect of irradiation. Even
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though aggressive radiotherapy is best, some neoplasms can be treated palliatively with less than curative doses to produce tumor regression, stages of tumor growth, or relief of pain enabling the animal to be more comfortable for a short period of time. The rate of tumor regression during or following radiation therapy has not proved helpful prognostically. For example, a neoplasm that regresses completely during irradiation may recur just as rapidly several weeks later. Conversely, a neoplasm may not change in size following irradiation and remain unchanged for years, representing a cure. There is a paucity of published data concerning the effectiveness of radiotherapy in treating neoplasms in the dog and cat; therefore the probability of cure cannot be stated precisely. At present, most tumors which have been treated with irradiation have been either difficult or impossible to remove surgically or have recurred following previous surgery. Histological and clinical staging of tumors and radiation therapy protocols have not been uniform. Clinically, it is obvious that cure rates differ for the individual tumor based on numerous factors such as patient health, location, and clinical and histological staging of the tumor. The following tumors appear to be the most radioresponsive: perianal adenoma, perianal adenocarcinoma, squamous cell carcinoma, adenocarcinoma, ameloblastoma, mast cell sarcoma, and transmissible venereal tumor. Fibrosarcoma and malignant melanoma are less radioresponsive but may be effictively controlled for several to many months. Carcinomas in general are more radioresponsive than are sarcomas. It is our experience that following radiotherapy in dogs and cats, one year survival data without clinical evidence of tumor recurrence is approximately 50 per cent for squamous cell carcinoma, perianal adenomas, and perianal adenocarcinomas, and approximately 40 per cent for mast cell tumors. Postoperative irradiation of nasal adenocarcinoma and squamous cell carcinoma in dogs has been successful in controlling most tumors and extending the animal's life an additional 5 to 14 months longer than is reported when only surgery is done. Approximately 50 per cent of the fibrosarcomas can be controlled for 6 to 14 months. Of six oral malignant melanomas in dogs treated after recurrence following surgery, irradiation successfully produced regression and control for as long as 18 months in one dog and three years in another dog. A recently completed study reports the percentage control of 241 canine tumors for at least one year without tumor recurrence following radiation therapy doses of 3000 rads and higher. 4 The control was 4 7 per cent for perianal tumors, 52 per cent for mast cell tumors and squamous cell carcinomas, 10 per cent for adenocarcinomas, and 27 per cent for fibrosarcomas.
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FOLLOW-UP When one looks critically at the medical literature, it is not difficult to find numerous articles reporting on the efficacy of accepted modes of treating human cancer as well as suggestions for new ways in which to handle certain aspects of this dread conglomerate of diseases. These reports can be found in both general medical journals and specialty journals. It is apparent in looking critically at the medical literature that articles reporting on the efficacy of various modes of treatment of animal cancer are limited. The reason for this discrepancy is related to a number of factors. First, cancer is not a pleasant entity to deal with and therefore has not been attacked enthusiastically by the majority of veterinarians. Second, surgical removal of the tumor has remained the principal method of dealing with animal cancer. Although this same practice occurred in human medicine, physicians have recorded data relative to tumor type and success rate while too often the veterinarian has failed to accumulate data concerning the outcome of the patient. Even veterinarians who have kept complete organized records have apparently hesitated to make this information available through publication. Finally, the fact that cancer can be cured, or at least put into longterm remission in a significant number of instances, is not fully realized and probably too often our option to perform active euthanasia is exercised prematurely. Why is it important to record data on the efficacy of cancer therapy in animals? A number of reasons should stimulate us to take an organized approach in record keeping and data retrieval. First, it would provide a service of higher quality to our clients. Companion animals develop cancer at an incidence of approximately 381 new cases per l 00,000 dogs per year and 156 new cases per 100,000 cats per year. 7 By the time animals do develop cancer, they are generally elderly and have become an integral part of the family. Owners of these animals usually are very willing to support an attempt to save or prolong the life rather than have euthanasia performed if such an option is offered to them. At present, many such people expect top quality medical care for their pets. If no data exist on the efficacy of a particular type of therapy, there can be no way of determining how to modify the treatment protocol or whether a modification which has been instituted is beneficial or detrimental. Another reason it is important to accumulate data relative to cancer therapy is that the information may be helpful to physician colleagues in terms of modifying their protocols for the treatment of cancer in man. The information that we compile is of great potential value. There is no justification for the utilization of a procedure without some knowledge, or at least a plan to accumulate knowledge, regarding its efficacy. Every veterinarian treating cancer patients should strive to
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obtain complete follow-up information so that the treatment protocol utilized can be evaluated. Logistically, this can be accomplished either by a phone call to local clients or a questionnaire mailed to more distant clients. At the University of Pennsylvania, each client whose animal receives radiation therapy is sent a personal letter containing a selfaddressed stamped questionnaire inquiring about a number of aspects of the radiation treatment. The letter is sent to each client every six months until contact is lost or the final status of the animal is known. Client response to this form of questionnaire is excellent. A certain amount of effort and expense is associated with this type of data retrieval system; however, these factors are insignificant when compared with the actual value of the information obtained. · The importance of following up each case treated cannot be emphasized strongly enough. Compilation and reporting of data concerning the efficacy of cancer treatment must be done if therapy of cancer m animals is to be accomplished in a scientifically acceptable fashion.
NEW RADIOTHERAPY MODALITIES As the art and science of human radiotherapy progress, much attention is being given to mew modalities in the hope of increasing the existing cure rates. Data obtained from using these new modalities on spontaneous tumors in domestic animals would be an extremely valuable contribution to medical science. The three modalities receiving the most attention at the present time are neutron radiotherapy, 7T-meson radiotherapy, and hyperthermia. Neutron Radiotherapy
Neutrons are uncharged particles with a mass approximately 200 times greater than an electron. Neutrons may be well suited as a radiotherapy modality for two reasons.!! (l) They kill hypoxic cells almost as efficiently as they kill oxygenated tumor cells. This is not the case for xrays or gamma rays. Hypoxic cells require two to three times the amount of x-irradiation or gamma irradiation to be killed when compared with oxygenated cells. Hypoxic tumor cells may become reoxygenated and lead to recurrence of the tumor; therefore neutrons are more efficient in eliminating the hypoxic tumor cells which may lead to tumor regrowth. (2) Neutrons produce less radiation damage which is capable of being repaired in the intertreatment interval; therefore the net effect of fractionation schemes of neutron irradiation is less likely to vary as a result of the frequency of the fractions when compared with xirradiation or gamma irradiation.
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7T-Meson Radiotherapy Negative 1T mesons are negatively charged particles having a mass 273 times greater than the mass of an electron. The Los Alamos Scientific Laboratory of the University of California at Los Alamos, New Mexico is a recently completed facility. dedicated entirely to studying the physical, biological, and medical applications of 1r-mesons. Negative 1T mesons have attracted considerable interest as a radiotherapy modality because of their property of producing a greater deposition of energy at a certain depth into the body rather than at or near the surface as is the case with x-irradiation or gamma irradiation. This naturally would be desirable in cases in which the tumor was not located at the surface of the body.
Hyperthermia Hyperthermia implies raiSing the temperature of tissues and has been advocated as a useful cancer therapy modality both alone and in combination with ionizing radiation for the following reasons :9 (l) heat suppresses the ability of cells to repair radiation damage; (2) heat enhances the expression of lethal radiation damage; (3) tumor cells may be more heat-sensitive than are normal cells; and (4) hypoxic cells are more heat-sensitive than are aerobic cells.
REFERENCES I. Biery, D. N.: Radiation therapy in dermatology. In Kirk, R. W. (ed.): Current Veterinary Therapy VI. Philadelphia, W. B. Saunders Co., 1977. 2. Dorn, C. R., Taylor, D. 0. N., Schneider, R., eta!.: Survey of animal neoplasms in Alameda and Contra Costa Counties, California. II. Cancer morbidity in dogs and cats from Alameda County. J. Nat. Cancer Inst., 40:307-318, 1968. 3. (~illette, E. L.: Indications and selection of patients for radiation therapy. VET. Cux. NORTH AM., 4:889-896, 1975. -!. Gillette, E. L.: Radiation oncology. In Kirk, R. W. (ed): Current Veterinary Therapy VI. Philadelphia, W. B. Saunders Co., 1977. 5. Gilette, E. L.: Veterinary radiotherapy. J.A.V.M.A., 157:1707-1712, 1972. 6. Hall, E . .J.: Radiobiology for the Radiologist. Hagerstown, Md., Harper and Row, Inc., 1973. 7. Hilaris, B. S.: A Manual for Brachytherapy. New York, Memorial Sloan Kettering Cancer Center. 8. Silver, I. A.: Use of radiotherapy for the treatment of malignant neoplasms. J. Small Anim. Pract., 13:351-358, 1972. 9. Thrall, D. E., Gerweck, L. E., Gillette, E. L., eta!.: Response of cells in vitro and tissues in vivo to hyperthermia and x-irradiation. Adv. Radiation Bioi., 6:211-227, 1976.
Department of Anatomy and Radiology College of Veterinary Medicine University of Georgia Athens, Georgia 30602